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Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy.

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cam.issuedOnline2013-12-10
dc.contributor.authorLin, Qun
dc.contributor.authorHuang, Yan
dc.contributor.authorBooth, Carmen J
dc.contributor.authorHaase, Volker H
dc.contributor.authorJohnson, Randall S
dc.contributor.authorCeleste Simon, M
dc.contributor.authorGiordano, Frank J
dc.contributor.authorYun, Zhong
dc.contributor.orcidJohnson, Randall [0000-0002-4084-6639]
dc.date.accessioned2020-03-14T00:30:29Z
dc.date.available2020-03-14T00:30:29Z
dc.date.issued2013-12-10
dc.description.abstractBACKGROUND: Obesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia-signaling pathway plays an essential role in the development of obesity-associated cardiomyopathy. METHODS AND RESULTS: Using a mouse model in which the hypoxia-inducible factor (HIF) pathway is activated by deletion of the von Hippel-Lindau gene specifically in adipocytes, we found that mice with adipocyte-von Hippel-Lindau deletion developed lethal cardiac hypertrophy. HIF activation in adipocytes results in overexpression of key cardiomyopathy-associated genes in adipose tissue, increased serum levels of several proinflammatory cytokines including interleukin-1β and monocyte chemotactic protein-1, and activation of nuclear factor-κB and nuclear factor of activated T cells in the heart. Interestingly, genetic deletion of Hif2a, but not Hif1a, was able to rescue cardiac hypertrophy and abrogate adipose inflammation. CONCLUSION: We have discovered a previously uncharacterized mechanism underlying a critical and direct role of the adipocyte HIF-2 transcription factor in the development of adipose inflammation and pathological cardiac hypertrophy.
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.50510
dc.identifier.eissn2047-9980
dc.identifier.issn2047-9980
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/303422
dc.languageeng
dc.language.isoeng
dc.publisherOvid Technologies (Wolters Kluwer Health)
dc.publisher.urlhttp://dx.doi.org/10.1161/jaha.113.000548
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectadipocytes
dc.subjectcardiomyopathy
dc.subjecthypoxia
dc.subjectinflammation
dc.subjectobesity
dc.subjectAdipocytes
dc.subjectAnimals
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.subjectCardiomegaly
dc.subjectCytokines
dc.subjectDisease Models, Animal
dc.subjectGene Expression Regulation
dc.subjectGenetic Predisposition to Disease
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.subjectInflammation Mediators
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectMice, Transgenic
dc.subjectMyocytes, Cardiac
dc.subjectPhenotype
dc.subjectSignal Transduction
dc.subjectTime Factors
dc.subjectVon Hippel-Lindau Tumor Suppressor Protein
dc.titleActivation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy.
dc.typeArticle
prism.issueIdentifier6
prism.publicationDate2013
prism.publicationNameJ Am Heart Assoc
prism.startingPagee000548
prism.volume2
pubs.funder-project-idWellcome Trust (092738/Z/10/Z)
rioxxterms.licenseref.startdate2013-12-10
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1161/JAHA.113.000548

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